Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline

The effect of paroxetine or sertraline on steady-state plasma concentration s of clozapine and its major metabolites was studied in 17 patients with sc hizophrenia or schizoaffective disorder stabilized on clozapine therapy (20 0-400 mg/day). In order to treat negative symptomatology or concomitant dep ression, 9 patients received additional paroxetine (20-40mg/day) and 8 pati ents sertraline (50-100mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased signifi cantly by 31% (p < 0.01) and by 20% (p < 0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapin e/ clozapine and clozapine N-oxide/clozapine ratios were not modified durin g paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeuti c doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-d emethylation and N-oxidation. While sertraline may be added safely to patie nts on maintenance treatment with clozapine, careful clinical observation a nd monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.